cdc-48.1

id: P54811
gene_symbol: cdc-48.1
aliases:
  - C06A1.1
  - p97
  - VCP homolog 1
  - TERA1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:6239
  label: Caenorhabditis elegans
description: >-
  CDC-48.1 is the C. elegans ortholog of mammalian p97/VCP, a highly conserved AAA+ ATPase
  that functions as a molecular chaperone. It forms homohexameric or heterohexameric rings
  (with CDC-48.2) and uses ATP hydrolysis to generate mechanical force for unfolding
  substrate proteins, disassembling protein complexes, and disaggregating protein aggregates.
  CDC-48.1 is essential for ER-associated degradation (ERAD), working with UFD-1/NPL-4
  adaptors to extract misfolded proteins from the ER for proteasomal degradation. It also
  functions in DNA replication by promoting degradation of CDT-1 and disassembly of
  replication complexes, cell cycle progression, chromatin-associated protein degradation,
  mitotic spindle disassembly, and spermatogenesis regulation. CDC-48.1 works with various
  UBX domain-containing cofactors (UBXN-1 through UBXN-6) that determine substrate specificity.
existing_annotations:
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 localizes to the nucleus where it functions in DNA replication,
      chromatin-associated degradation, and cell cycle regulation (PMID:22735043, PMID:26842564).
    action: ACCEPT
    reason: >-
      Nuclear localization is well-supported by phylogenetic inference from orthologs
      and directly confirmed by experimental evidence in C. elegans showing CDC-48
      associates with chromatin and functions in nuclear processes.
    supported_by:
      - reference_id: PMID:22735043
        supporting_text: "CDC-48/p97 is a AAA (ATPases associated with diverse cellular activities) chaperone involved in protein conformational changes such as the disassembly of protein complexes"
      - reference_id: PMID:26842564
        supporting_text: "cellular fractionation of C. elegans embryonic lysates confirmed high abundance of UBXN-3, CDC-48 and CDT-1 in purified nuclei"

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      ATP hydrolysis activity is the core enzymatic function of CDC-48.1. The protein
      contains two AAA ATPase domains (D1 and D2) that hydrolyze ATP with positive
      cooperativity (PMID:21454554, PMID:18782221).
    action: ACCEPT
    reason: >-
      This is a core molecular function of CDC-48.1, confirmed by multiple direct
      biochemical assays showing ATPase activity with defined kinetic parameters.
    supported_by:
      - reference_id: PMID:21454554
        supporting_text: "The ATPase activity of the N-terminal AAA domain was very low at physiological temperature, whereas the C-terminal AAA domain showed high ATPase activity in a coordinated fashion with positive cooperativity"
      - reference_id: PMID:18782221
        supporting_text: "CDC-48.1 and CDC-48.2 suppress the aggregation of a huntingtin (Htt) exon1 fragment containing an expanded polyQ repeat in vitro"

- term:
    id: GO:0051228
    label: mitotic spindle disassembly
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 is involved in mitotic spindle disassembly through its role in
      chromatin decondensation and nuclear envelope re-assembly at the end of mitosis.
    action: ACCEPT
    reason: >-
      Phylogenetically conserved function supported by IBA from yeast Cdc48 and
      consistent with C. elegans functional data showing CDC-48 is required for
      post-mitotic chromatin decondensation.
    supported_by:
      - reference_id: PMID:18728180
        supporting_text: "Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms"

- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 localizes to the cytosol where it functions in ERAD and
      proteasomal degradation pathways (PMID:16647269, PMID:20977550).
    action: ACCEPT
    reason: >-
      Cytosolic localization is phylogenetically conserved and confirmed by
      experimental studies in C. elegans showing CDC-48 functions in cytoplasmic
      protein degradation pathways.
    supported_by:
      - reference_id: PMID:20977550
        supporting_text: "UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in spermatocytes but not mature sperm"

- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 is a key component of the ubiquitin-proteasome system, binding
      polyubiquitinated substrates and facilitating their delivery to the proteasome
      for degradation (PMID:16647269, PMID:21673654).
    action: ACCEPT
    reason: >-
      This is a core function of p97/VCP family proteins. CDC-48.1 extracts
      ubiquitinated substrates from complexes and membranes for proteasomal
      degradation, a function conserved from yeast to humans.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "the AAA ATPase p97/VCP/CDC48 is required in this pathway for protein dislocation across the ER membrane and subsequent ubiquitin dependent degradation by the 26S proteasome in the cytosol"
      - reference_id: PMID:21673654
        supporting_text: "EGF signalling alters protein homoeostasis in adults by increasing UPS activity and polyubiquitination, while decreasing protein aggregation"

- term:
    id: GO:0031593
    label: polyubiquitin modification-dependent protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 binds Lys-48-linked polyubiquitin chains on substrate proteins,
      enabling their extraction and delivery to the proteasome (PMID:16647269).
    action: ACCEPT
    reason: >-
      This is the substrate recognition mechanism for CDC-48/p97 proteins.
      Binding to polyubiquitinated substrates is mediated through adaptor
      proteins and is essential for ERAD and other degradation pathways.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "the AAA ATPase p97/VCP/CDC48 is required in this pathway for protein dislocation across the ER membrane and subsequent ubiquitin dependent degradation by the 26S proteasome"

- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 is required for retro-translocation of misfolded proteins from
      the ER lumen to the cytosol for ERAD (PMID:16647269).
    action: ACCEPT
    reason: >-
      This is a core function of CDC-48/p97 in ERAD. The protein provides
      the ATP-dependent force needed to extract substrates through the
      ER membrane retrotranslocon.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "these data suggest an evolutionarily conserved retro-translocation machinery at the endoplasmic reticulum"

- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 forms a complex with UFD-1 and NPL-4 adaptors, the C. elegans
      equivalent of the mammalian VCP-NPL4-UFD1 complex (PMID:16647269, PMID:20977550).
    action: ACCEPT
    reason: >-
      The CDC-48/UFD-1/NPL-4 complex is phylogenetically conserved and has
      been directly demonstrated in C. elegans through co-immunoprecipitation.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "both p97 homologs interact with UFD-1/NPL-4 in a similar CDC-48(UFD-1/NPL-4) complex"
      - reference_id: PMID:26842564
        supporting_text: "UBXN-3 and NPL-4 have been shown to simultaneously bind to single CDC-48 hexamers in vivo"

- term:
    id: GO:0097352
    label: autophagosome maturation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      CDC-48.1 is involved in autophagosome maturation, a phylogenetically
      conserved function of p97/VCP proteins.
    action: ACCEPT
    reason: >-
      p97/VCP is known to function in autophagy in mammals and other organisms.
      The IBA annotation reflects this conserved function.

- term:
    id: GO:0000166
    label: nucleotide binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      CDC-48.1 contains two AAA ATPase domains that bind ATP. This general
      term is captured by the more specific ATP binding annotation.
    action: ACCEPT
    reason: >-
      Nucleotide binding is an accurate but general descriptor. CDC-48.1
      binds ATP through its two AAA domains. While redundant with more
      specific terms, this IEA annotation is not incorrect.

- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      CDC-48.1 binds ATP through its two AAA ATPase domains (D1 and D2).
      ATP binding to D1 induces conformational changes that regulate D2
      ATPase activity (PMID:21454554, PMID:24055316).
    action: ACCEPT
    reason: >-
      ATP binding is essential for CDC-48.1 function and is inferred
      correctly from InterPro domain annotations (AAA ATPase domains).
    supported_by:
      - reference_id: PMID:21454554
        supporting_text: "p97 is composed of two conserved AAA (ATPases associated with diverse cellular activities) domains, which form a tandem hexameric ring"

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      Nuclear localization is inferred by machine learning and confirmed
      experimentally (PMID:22735043, PMID:18728180).
    action: ACCEPT
    reason: >-
      This is a duplicate of the IBA annotation but with IEA evidence.
      Both are correct as CDC-48.1 localizes to both cytoplasm and nucleus.
    supported_by:
      - reference_id: PMID:22735043
        supporting_text: "CDC-48/p97 is required for proper meiotic chromosome segregation via controlling AIR-2/Aurora B kinase localization in Caenorhabditis elegans"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      CDC-48.1 is present in the cytoplasm where it functions in ERAD
      and proteasomal degradation (PMID:16647269, PMID:20977550).
    action: ACCEPT
    reason: >-
      Cytoplasmic localization is correctly inferred from UniProt
      subcellular location data and confirmed by experimental studies.
    supported_by:
      - reference_id: PMID:20977550
        supporting_text: "UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in spermatocytes but not mature sperm"

- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CDC-48.1 associates with the ER membrane during ERAD to extract
      misfolded proteins for degradation (PMID:16647269).
    action: ACCEPT
    reason: >-
      ER membrane association is consistent with CDC-48.1's role in
      retro-translocation during ERAD.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "the AAA ATPase p97/VCP/CDC48 is required in this pathway for protein dislocation across the ER membrane"

- term:
    id: GO:0009792
    label: embryo development ending in birth or egg hatching
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CDC-48.1 is essential for embryonic development in C. elegans.
      RNAi knockdown causes embryonic lethality, especially when combined
      with cdc-48.2 depletion (PMID:16647269, PMID:18728180).
    action: KEEP_AS_NON_CORE
    reason: >-
      While CDC-48.1 is required for embryonic development, this is a
      pleiotropic phenotype resulting from its core functions in ERAD,
      DNA replication, and cell cycle control rather than a primary
      developmental function.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen"
      - reference_id: PMID:18728180
        supporting_text: "These developmental defects result from activation of the DNA replication checkpoint caused by replication stress"

- term:
    id: GO:0010498
    label: proteasomal protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CDC-48.1 facilitates proteasomal degradation by extracting
      ubiquitinated substrates and delivering them to the proteasome.
    action: ACCEPT
    reason: >-
      This is a core function of CDC-48.1, closely related to its
      role in ERAD and ubiquitin-dependent protein degradation.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "subsequent ubiquitin dependent degradation by the 26S proteasome in the cytosol"

- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      CDC-48.1 has ATP hydrolase (ATPase) activity through its AAA domains.
      This general term is subsumed by the more specific ATP hydrolysis activity.
    action: ACCEPT
    reason: >-
      Hydrolase activity is correctly inferred from domain annotations.
      While redundant with ATP hydrolysis activity, it is not incorrect.

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      ATP hydrolysis activity is inferred from AAA ATPase domain annotations
      and confirmed by direct enzymatic assays (PMID:21454554).
    action: ACCEPT
    reason: >-
      Correctly inferred core function, also supported by IDA and IBA evidence.
    supported_by:
      - reference_id: PMID:21454554
        supporting_text: "We characterized the ATP hydrolysis mechanism of CDC-48.1, a p97 homolog of Caenorhabditis elegans"

- term:
    id: GO:0017111
    label: ribonucleoside triphosphate phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This term is a parent of ATP hydrolysis activity. CDC-48.1 specifically
      hydrolyzes ATP, not other NTPs.
    action: MODIFY
    reason: >-
      While technically correct as a parent term of ATP hydrolysis activity,
      this annotation is too general. CDC-48.1 is an ATPase; there is no
      evidence it has significant activity on other ribonucleoside triphosphates.
    proposed_replacement_terms:
      - id: GO:0016887
        label: ATP hydrolysis activity

- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CDC-48.1 regulates protein localization, particularly chromatin-associated
      proteins like CDT-1 and AIR-2 (PMID:26842564, PMID:22735043).
    action: ACCEPT
    reason: >-
      CDC-48.1 regulates the localization of multiple substrates through
      its segregase activity, extracting proteins from complexes and
      promoting their degradation or relocalization.
    supported_by:
      - reference_id: PMID:26842564
        supporting_text: "UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes"

- term:
    id: GO:0034976
    label: response to endoplasmic reticulum stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CDC-48.1 is essential for the response to ER stress through its role
      in ERAD. Depletion causes accumulation of misfolded proteins and
      induction of the unfolded protein response (PMID:16647269).
    action: ACCEPT
    reason: >-
      CDC-48.1 is a key component of the ERAD pathway that resolves ER
      stress by eliminating misfolded proteins.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen"

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      CDC-48.1 forms homohexamers through self-association (PMID:18782221,
      PMID:24055316).
    action: ACCEPT
    reason: >-
      Homohexamer formation is essential for CDC-48.1 function and has
      been directly demonstrated biochemically.
    supported_by:
      - reference_id: PMID:24055316
        supporting_text: "p97 (also called VCP and CDC-48) is an AAA+ chaperone, which consists of a substrate/cofactor-binding N domain and two ATPase domains (D1 and D2), and forms a homo-hexameric ring"
      - reference_id: PMID:21454554
        supporting_text: "p97 is composed of two conserved AAA (ATPases associated with diverse cellular activities) domains, which form a tandem hexameric ring"

- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: >-
      CDC-48.1 localizes to the perinuclear region in spermatocytes (PMID:20977550).
    action: ACCEPT
    reason: >-
      Perinuclear localization has been directly observed by immunofluorescence.
    supported_by:
      - reference_id: PMID:20977550
        supporting_text: "UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in spermatocytes but not mature sperm"

- term:
    id: GO:0098796
    label: membrane protein complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: >-
      This term suggests CDC-48.1 is part of a membrane protein complex,
      which is not its primary form of association.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      While CDC-48.1 associates with the ER membrane during ERAD, it is
      primarily a soluble cytoplasmic/nuclear protein that transiently
      associates with membranes. The VCP-NPL4-UFD1 complex is the
      appropriate complex annotation. This annotation is misleading.

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:14704431
  review:
    summary: >-
      Protein binding detected in high-throughput Y2H interactome mapping study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      "Protein binding" is too general and uninformative. CDC-48.1 has specific
      binding partners including UBX domain proteins, UFD-1, NPL-4, and
      substrates. High-throughput Y2H provides limited mechanistic insight.
    supported_by:
      - reference_id: PMID:14704431
        supporting_text: "more than 4000 interactions were identified from high-throughput, yeast two-hybrid (HT=Y2H) screens"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19123269
  review:
    summary: >-
      Protein binding with CDC-48.2 (P54812) detected in Y2H interactome mapping.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      General protein binding is uninformative. The interaction with CDC-48.2
      reflects heterohexamer formation, but this is better captured by the
      identical protein binding annotation.
    supported_by:
      - reference_id: PMID:19123269
        supporting_text: "We present an expanded Caenorhabditis elegans protein-protein interaction network, or \"interactome\" map derived from testing a matrix of ~ 10,000 × ~ 10,000 proteins using a highly specific high-throughput yeast two-hybrid system"

- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:24055316
  review:
    summary: >-
      High-speed atomic force microscopy study demonstrating CDC-48.1
      homohexamer formation and ATP-dependent conformational changes.
    action: ACCEPT
    reason: >-
      This study provides direct structural evidence for CDC-48.1
      self-association into hexameric rings, a core property of the protein.
    supported_by:
      - reference_id: PMID:24055316
        supporting_text: "we studied the conformational changes of hexameric CDC-48.1, a Caenorhabditis elegans p97 homolog, using high-speed atomic force microscopy"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25721663
  review:
    summary: >-
      Study characterizing CDC-48 interaction with UFD-2 and UFD-3 C-terminal
      adaptors in regulation of polyglutamine aggregation.
    action: MODIFY
    reason: >-
      The study provides specific information about binding to UFD-3 adaptor.
      A more specific term would be informative.
    proposed_replacement_terms:
      - id: GO:0044877
        label: protein-containing complex binding
    supported_by:
      - reference_id: PMID:25721663
        supporting_text: "CDC-48 preferentially interacts with UFD-3 in Caenorhabditis elegans"

- term:
    id: GO:0032436
    label: positive regulation of proteasomal ubiquitin-dependent protein catabolic process
  evidence_type: IMP
  original_reference_id: PMID:21673654
  review:
    summary: >-
      CDC-48.1 promotes proteasomal degradation as part of the EGF signaling
      pathway that modulates lifespan through increased UPS activity.
    action: ACCEPT
    reason: >-
      This captures CDC-48.1's role in facilitating proteasomal degradation,
      demonstrated by mutant phenotype analysis.
    supported_by:
      - reference_id: PMID:21673654
        supporting_text: "EGF signalling alters protein homoeostasis in adults by increasing UPS activity and polyubiquitination, while decreasing protein aggregation"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20977550
  review:
    summary: >-
      Study demonstrating CDC-48 interactions with multiple UBX cofactors
      (UBXN-1 through UBXN-6) and their role in spermatogenesis.
    action: MODIFY
    reason: >-
      This reflects specific binding to UBX domain adaptor proteins.
      More specific annotation would be preferable.
    proposed_replacement_terms:
      - id: GO:0044877
        label: protein-containing complex binding
    supported_by:
      - reference_id: PMID:20977550
        supporting_text: "All six UBXN proteins directly interacted with CDC-48.1 and CDC-48.2"

- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23649807
  review:
    summary: >-
      Study showing UBXN-2 interaction with CDC-48 regulates Aurora A
      at centrosomes during mitosis.
    action: MODIFY
    reason: >-
      This reflects specific binding to UBXN-2 adaptor protein in
      the context of centrosome regulation.
    proposed_replacement_terms:
      - id: GO:0044877
        label: protein-containing complex binding
    supported_by:
      - reference_id: PMID:23649807
        supporting_text: "UBXN-2 and CDC-48 limit AIR-1 accumulation at centrosomes in prophase"

- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:20977550
  review:
    summary: >-
      Direct evidence for CDC-48.1 forming a complex with UFD-1 and NPL-4
      adaptors in C. elegans.
    action: ACCEPT
    reason: >-
      This is well-supported by co-immunoprecipitation and functional
      studies showing the CDC-48/UFD-1/NPL-4 complex is essential for
      multiple cellular processes.
    supported_by:
      - reference_id: PMID:26842564
        supporting_text: "UBXN-3 and NPL-4 have been shown to simultaneously bind to single CDC-48 hexamers in vivo"

- term:
    id: GO:0044877
    label: protein-containing complex binding
  evidence_type: IDA
  original_reference_id: PMID:20977550
  review:
    summary: >-
      CDC-48.1 binds to protein complexes containing UBXN adaptors
      and substrates for extraction and processing.
    action: ACCEPT
    reason: >-
      CDC-48.1's segregase function involves binding to and disassembling
      protein complexes, which is the molecular basis for this annotation.
    supported_by:
      - reference_id: PMID:20977550
        supporting_text: "these results suggest that UBXN-1, UBXN-2 and UBXN-3 are redundant cofactors for CDC-48/p97 and control spermatogenesis via the degradation of TRA-1A"

- term:
    id: GO:0045977
    label: positive regulation of mitotic cell cycle, embryonic
  evidence_type: IGI
  original_reference_id: PMID:26842564
  review:
    summary: >-
      CDC-48.1 promotes embryonic cell cycle progression through its role
      in DNA replication and degradation of replication factors.
    action: ACCEPT
    reason: >-
      The study demonstrates that CDC-48/UBXN-3 function is required
      for proper S phase progression and cell cycle timing.
    supported_by:
      - reference_id: PMID:26842564
        supporting_text: "progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes"

- term:
    id: GO:1905634
    label: regulation of protein localization to chromatin
  evidence_type: IGI
  original_reference_id: PMID:26842564
  review:
    summary: >-
      CDC-48.1 regulates the chromatin association of DNA replication
      factors including CDT-1 and CDC-45/GINS complex components.
    action: ACCEPT
    reason: >-
      The study directly demonstrates CDC-48 regulates chromatin
      association of multiple replication factors.
    supported_by:
      - reference_id: PMID:26842564
        supporting_text: "inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics"

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22735043
  review:
    summary: >-
      Direct observation of CDC-48 localization in the nucleus during
      meiosis and mitosis in C. elegans.
    action: ACCEPT
    reason: >-
      Nuclear localization directly demonstrated by fluorescence microscopy.
    supported_by:
      - reference_id: PMID:22735043
        supporting_text: "CDC-48/p97 is required for proper meiotic chromosome segregation via controlling AIR-2/Aurora B kinase localization"

- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: PMID:22735043
  review:
    summary: >-
      CDC-48 localizes to the nucleoplasm where it regulates meiotic
      chromosome segregation.
    action: ACCEPT
    reason: >-
      Nucleoplasmic localization is consistent with CDC-48's role in
      regulating chromatin-associated proteins during cell division.
    supported_by:
      - reference_id: PMID:22735043
        supporting_text: "CDC-48s control the restricted localization of AIR-2 to the cohesion sites of homologous chromatids in meiosis I"

- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22735043
  review:
    summary: >-
      CDC-48 is present in the cytoplasm as shown by immunofluorescence studies.
    action: ACCEPT
    reason: >-
      Cytoplasmic localization directly observed.
    supported_by:
      - reference_id: PMID:22735043
        supporting_text: "CDC-48/p97 is a AAA (ATPases associated with diverse cellular activities) chaperone involved in protein conformational changes such as the disassembly of protein complexes"

- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:20977550
  review:
    summary: >-
      CDC-48 localizes to the perinuclear region in spermatocytes.
    action: ACCEPT
    reason: >-
      Perinuclear localization directly demonstrated by immunofluorescence.
    supported_by:
      - reference_id: PMID:20977550
        supporting_text: "UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in spermatocytes but not mature sperm"

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:18854144
  review:
    summary: >-
      This reference studies CDC-48.3, a distinct Afg2/Spaf subfamily member,
      not CDC-48.1. However, ATP hydrolysis activity for CDC-48.1 is well-established
      by other references (PMID:21454554, PMID:18782221).
    action: ACCEPT
    reason: >-
      Although PMID:18854144 specifically studies CDC-48.3 (not CDC-48.1), the
      annotation of ATP hydrolysis activity is correct for CDC-48.1 based on
      other direct enzymatic assays (see PMID:21454554).
    supported_by:
      - reference_id: PMID:18854144
        supporting_text: "This screen uncovered a member of the Afg2/Spaf subfamily of Cdc48-like AAA ATPases as an essential inhibitor of AIR-2 stability and activity"

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:18782221
  review:
    summary: >-
      Biochemical characterization of CDC-48.1 ATPase activity in the
      context of polyQ aggregate suppression.
    action: ACCEPT
    reason: >-
      Direct enzymatic assay demonstrating ATPase activity.
    supported_by:
      - reference_id: PMID:18782221
        supporting_text: "CDC-48.1 and CDC-48.2 suppress the aggregation of a huntingtin (Htt) exon1 fragment containing an expanded polyQ repeat in vitro"

- term:
    id: GO:0016887
    label: ATP hydrolysis activity
  evidence_type: IDA
  original_reference_id: PMID:21454554
  review:
    summary: >-
      Detailed biochemical characterization of CDC-48.1 ATPase mechanism
      showing positive cooperativity between the two AAA domains.
    action: ACCEPT
    reason: >-
      Comprehensive enzymatic analysis with kinetic parameters and
      mutagenesis defining the catalytic mechanism.
    supported_by:
      - reference_id: PMID:21454554
        supporting_text: "The ATPase activity of the N-terminal AAA domain was very low at physiological temperature, whereas the C-terminal AAA domain showed high ATPase activity in a coordinated fashion with positive cooperativity"

- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:18728180
  review:
    summary: >-
      Nuclear localization of CDC-48 demonstrated in the context of
      DNA replication and cell cycle studies.
    action: ACCEPT
    reason: >-
      Nuclear localization directly observed, consistent with CDC-48's
      role in DNA replication control.
    supported_by:
      - reference_id: PMID:18728180
        supporting_text: "Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms"

- term:
    id: GO:0009792
    label: embryo development ending in birth or egg hatching
  evidence_type: IGI
  original_reference_id: PMID:16647269
  review:
    summary: >-
      CDC-48.1 is required for embryonic development, with combined
      cdc-48.1/cdc-48.2 depletion causing embryonic lethality.
    action: KEEP_AS_NON_CORE
    reason: >-
      Embryonic lethality is a pleiotropic phenotype reflecting CDC-48's
      essential roles in ERAD, cell cycle, and proteostasis rather than
      a specific developmental function.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen"

- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: IPI
  original_reference_id: PMID:16647269
  review:
    summary: >-
      Physical interaction between CDC-48 and UFD-1 demonstrated,
      establishing the C. elegans CDC-48/UFD-1/NPL-4 complex.
    action: ACCEPT
    reason: >-
      Direct physical interaction evidence for complex formation.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "both p97 homologs interact with UFD-1/NPL-4 in a similar CDC-48(UFD-1/NPL-4) complex"

- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IGI
  original_reference_id: PMID:16647269
  review:
    summary: >-
      CDC-48.1 is a core component of the ERAD pathway in C. elegans,
      required for degradation of misfolded ER proteins.
    action: ACCEPT
    reason: >-
      ERAD is a primary, well-established function of CDC-48/p97 proteins
      across eukaryotes. Direct genetic evidence supports this in C. elegans.
    supported_by:
      - reference_id: PMID:16647269
        supporting_text: "these data suggest an evolutionarily conserved retro-translocation machinery at the endoplasmic reticulum"

references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:14704431
  title: A map of the interactome network of the metazoan C. elegans.
  findings: []
- id: PMID:16647269
  title: A conserved role of Caenorhabditis elegans CDC-48 in ER-associated protein degradation.
  findings:
    - statement: CDC-48.1 and CDC-48.2 interact with UFD-1/NPL-4 to form the conserved CDC-48(UFD-1/NPL-4) complex
      supporting_text: "both p97 homologs interact with UFD-1/NPL-4 in a similar CDC-48(UFD-1/NPL-4) complex"
    - statement: RNAi depletion induces ER stress and sensitivity to unfolded protein accumulation
      supporting_text: "RNAi mediated depletion of the corresponding genes induces ER stress resulting in hypersensitivity to conditions which induce increased levels of unfolded proteins in the ER lumen"
    - statement: Demonstrates evolutionarily conserved retro-translocation machinery at the ER
      supporting_text: "these data suggest an evolutionarily conserved retro-translocation machinery at the endoplasmic reticulum"
- id: PMID:18728180
  title: Cell cycle progression requires the CDC-48UFD-1/NPL-4 complex for efficient DNA replication.
  findings:
    - statement: CDC-48(UFD-1/NPL-4) complex is required for S phase progression
      supporting_text: "Our analysis of the CDC-48(UFD-1/NPL-4) complex identified a general role in S phase progression of mitotic cells essential for embryonic cell division and germline development of adult worms"
    - statement: Developmental defects result from DNA replication checkpoint activation
      supporting_text: "These developmental defects result from activation of the DNA replication checkpoint caused by replication stress"
    - statement: CDC-48 depletion causes reduced DNA content and decreased DNA synthesis
      supporting_text: "DNA content is strongly reduced in worms depleted for CDC-48, UFD-1, and NPL-4. In addition, these worms show decreased DNA synthesis"
- id: PMID:18782221
  title: p97 Homologs from Caenorhabditis elegans, CDC-48.1 and CDC-48.2, suppress the aggregate formation of huntingtin exon1 containing expanded polyQ repeat.
  findings:
    - statement: CDC-48.1 and CDC-48.2 directly bind huntingtin exon1 fragment
      supporting_text: "CDC-48.1 and CDC-48.2 bound the Htt exon1 fragment directly"
    - statement: Suppress SDS-insoluble aggregate formation independently of nucleotides
      supporting_text: "suppressed the formation of SDS-insoluble aggregates of Htt fragments containing 53 glutamine residues (HttQ53) independently of nucleotides"
    - statement: Modulate oligomeric states during aggregate formation suggesting chaperone function
      supporting_text: "CDC-48.1 and CDC-48.2 also modulated the oligomeric states of HttQ53 during the aggregate formation"
- id: PMID:18854144
  title: An Afg2/Spaf-related Cdc48-like AAA ATPase regulates the stability and activity of the C. elegans Aurora B kinase AIR-2.
  findings: []
- id: PMID:19123269
  title: Empirically controlled mapping of the Caenorhabditis elegans protein-protein interactome network.
  findings: []
- id: PMID:20977550
  title: Caenorhabditis elegans UBX cofactors for CDC-48/p97 control spermatogenesis.
  findings:
    - statement: All six UBXN proteins (UBXN-1 to UBXN-6) directly interact with CDC-48.1
      supporting_text: "All six UBXN proteins directly interacted with CDC-48.1 and CDC-48.2"
    - statement: UBXN-1, UBXN-2, UBXN-3 colocalize with CDC-48 in spermatocytes
      supporting_text: "UBXN-1, UBXN-2 and UBXN-3 colocalized with CDC-48 in spermatocytes but not mature sperm"
    - statement: UBX cofactors control spermatogenesis via TRA-1A degradation
      supporting_text: "these results suggest that UBXN-1, UBXN-2 and UBXN-3 are redundant cofactors for CDC-48/p97 and control spermatogenesis via the degradation of TRA-1A"
- id: PMID:21454554
  title: Positive cooperativity of the p97 AAA ATPase is critical for essential functions.
  findings:
    - statement: N-terminal AAA domain has low ATPase activity
      supporting_text: "The ATPase activity of the N-terminal AAA domain was very low at physiological temperature"
    - statement: C-terminal AAA domain shows high ATPase activity with positive cooperativity
      supporting_text: "the C-terminal AAA domain showed high ATPase activity in a coordinated fashion with positive cooperativity"
    - statement: Positive cooperativity is critical for essential functions
      supporting_text: "the positive cooperativity is critical for the essential functions of p97"
- id: PMID:21673654
  title: EGF signalling activates the ubiquitin proteasome system to modulate C. elegans lifespan.
  findings:
    - statement: EGF signaling upregulates UPS genes including CDC-48 pathway components
      supporting_text: "EGF signalling upregulates the expression of genes involved in the ubiquitin proteasome system (UPS)"
    - statement: UFD complex required for increased UPS activity in adults
      supporting_text: "SKR-5 and the E3/E4 ligases that comprise the ubiquitin fusion degradation (UFD) complex are required for the increase in UPS activity observed in adults"
    - statement: UPS activity regulates protein homeostasis and lifespan
      supporting_text: "EGF signalling alters protein homoeostasis in adults by increasing UPS activity and polyubiquitination, while decreasing protein aggregation"
- id: PMID:22735043
  title: CDC-48/p97 is required for proper meiotic chromosome segregation via controlling AIR-2/Aurora B kinase localization in Caenorhabditis elegans.
  findings:
    - statement: CDC-48s required for proper chromosome segregation during meiosis
      supporting_text: "CDC-48s are required for proper chromosome segregation during meiosis in C. elegans"
    - statement: Controls restricted localization of AIR-2 to cohesion sites of homologous chromatids
      supporting_text: "CDC-48s control the restricted localization of AIR-2 to the cohesion sites of homologous chromatids in meiosis I"
    - statement: Depletion causes expansion of AIR-2 signals over entire length of meiotic chromosomes
      supporting_text: "depletion of CDC-48s resulted in a significant expansion of signals for AIR-2 and phosphorylated histone H3 over the entire length of meiotic chromosomes"
- id: PMID:23649807
  title: The UBXN-2/p37/p47 adaptors of CDC-48/p97 regulate mitosis by limiting the centrosomal recruitment of Aurora A.
  findings:
    - statement: UBXN-2 interacts with CDC-48 to regulate centrosome maturation timing
      supporting_text: "UBXN-2 and CDC-48 limit AIR-1 accumulation at centrosomes in prophase"
- id: PMID:24055316
  title: High-speed atomic force microscopic observation of ATP-dependent rotation of the AAA+ chaperone p97.
  findings:
    - statement: CDC-48.1 forms hexameric ring
      supporting_text: "p97 (also called VCP and CDC-48) is an AAA+ chaperone, which consists of a substrate/cofactor-binding N domain and two ATPase domains (D1 and D2), and forms a homo-hexameric ring"
    - statement: ATP binding induces rotation of N-D1 ring relative to D2 ring
      supporting_text: "In the presence of ATP, the N-D1 ring repeatedly rotates ~23 ± 8° clockwise and resets relative to the D2 ring"
    - statement: Rotation induced by ATP binding to D2 domain
      supporting_text: "Mutational analysis reveals that this rotation is induced by ATP binding to the D2 domain"
- id: PMID:25721663
  title: Characterization of C-terminal adaptors, UFD-2 and UFD-3, of CDC-48 on the polyglutamine aggregation in C. elegans.
  findings:
    - statement: CDC-48 preferentially interacts with UFD-3 in C. elegans
      supporting_text: "CDC-48 preferentially interacts with UFD-3 in Caenorhabditis elegans"
- id: PMID:26842564
  title: Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression.
  findings:
    - statement: UBXN-3/FAF1 binds CDT-1 and ubiquitylated proteins to promote CDC-48-dependent turnover
      supporting_text: "UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes"
    - statement: CDC-48 and UBXN-3 associate with chromatin in nuclei
      supporting_text: "cellular fractionation of C. elegans embryonic lysates confirmed high abundance of UBXN-3, CDC-48 and CDT-1 in purified nuclei"
    - statement: Regulates disassembly of DNA replication factor complexes
      supporting_text: "promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes"
    - statement: Controls progression of DNA replication fork
      supporting_text: "progression of the DNA replication fork is coordinated by UBXN-3/FAF1"

core_functions:
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    description: >-
      Core enzymatic function enabling all CDC-48.1 activities. The protein uses
      ATP hydrolysis to generate mechanical force for substrate unfolding and
      complex disassembly.
  - molecular_function:
      id: GO:0031593
      label: polyubiquitin modification-dependent protein binding
    directly_involved_in:
      - id: GO:0036503
        label: ERAD pathway
    description: >-
      CDC-48.1 is essential for retro-translocation of misfolded proteins from the
      ER to the cytosol for proteasomal degradation, preventing ER stress and UPR activation.
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:0043161
        label: proteasome-mediated ubiquitin-dependent protein catabolic process
    in_complex:
      id: GO:0034098
      label: VCP-NPL4-UFD1 AAA ATPase complex
    description: >-
      CDC-48.1 extracts polyubiquitinated substrates from complexes and membranes
      and delivers them to the proteasome for degradation.
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:0051228
        label: mitotic spindle disassembly
    locations:
      - id: GO:0005634
        label: nucleus
    description: >-
      CDC-48.1 functions in post-mitotic processes including chromatin decondensation
      and nuclear envelope reassembly.
  - molecular_function:
      id: GO:0016887
      label: ATP hydrolysis activity
    directly_involved_in:
      - id: GO:1905634
        label: regulation of protein localization to chromatin
    locations:
      - id: GO:0005654
        label: nucleoplasm
    description: >-
      CDC-48.1 regulates chromatin association of DNA replication factors,
      controlling replication fork progression and cell cycle timing.

proposed_new_terms: []

suggested_questions:
  - question: What is the specific mechanism by which CDC-48.1 extracts AIR-2 from chromatin during meiosis?
  - question: How do different UBX domain adaptors determine CDC-48.1 substrate specificity?
  - question: What is the relationship between CDC-48.1 and CDC-48.2 in terms of functional redundancy and hetero-oligomer formation?

suggested_experiments:
  - description: Determine crystal structure of CDC-48.1 with different UBX adaptors to understand substrate selection
  - description: Identify the complete set of CDC-48.1 substrates using proximity labeling approaches
  - description: Test whether CDC-48.1 chaperone activity (ATP-independent) contributes to polyQ suppression in vivo